Therapeutic composition to treat lesions caused by herpes simplex virus

ABSTRACT

The present invention is generally directed toward therapeutic compositions for treating infections caused by Herpes Simplex Virus (“HSV”). The therapeutic compositions meet a long felt need in the art of providing a treatment for lesions that result from HSV that drastically reduce the duration of a cold sore when vesicles have already appeared and a treatment that will prevent the outbreak of a lesion and formation of vesicles when applied in the prodromal stage. The therapeutic compound comprises a mixture of Acyclovir (“ACV”), Penciclovir (“PCV”), and dimethyl sulfoxide (“DMSO”). The therapeutic compositions of the present invention include multiple formulations of the three active ingredients and may also include inactive ingredients and/or additional active ingredients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/116,112filed May 26, 2011, which is a continuation-in-part of application Ser.No. 12/884,698, filed Sep. 17, 2010, which claims the benefit of U.S.Provisional Application No. 61/243,251 filed Sep. 17, 2009, and which isalso a continuation-in-part of application Ser. No. PCT/US2010/049276filed Sep. 17, 2010, which claims the benefit of U.S. ProvisionalApplication No. 61/243,251 fifed Sep. 17, 2009, each of which is herebyincorporated in its entirety including all tables, figures and claims.

BACKGROUND OF THE INVENTION

Herpes Simplex Virus (“HSV”) is a family of viruses that infects a largeportion of the human population. HSV occurs in at least two well knownvarieties, particularly Herpes Simplex Virus 1 (“HSV-1”) and HerpesSimplex Virus 2 (“HSV-2”). It has been estimated that by the age offifty (50), eighty to ninety (80-90) percent of human beings carry HSV-1antibodies. It is also estimated that twenty to thirty (20-30) percentof the human population is infected with the HSV-2 virus. Once a personis infected, HSV remains in an inactive state in the body and may causerecurring lesions throughout the life of an infected person. The highprevalence of the human population that carries either HSV-1 or HSV-2leads to an ever increasing number of persons who experience lesionscaused by either HSV virus strain. The viruses often cause lesions onthe area surrounding the mouth and/or the genital area of those carryingHSV-1 or HSV-2.

A well known example of a HSV caused lesion is a cold sore or feverblister on or around the month of a person infected with HSV-1 or HSV-2.A cold sore is a lesion consisting of small blisters on the lip orsurrounding mouth that lasts from 5 to 14 days. These lesions are causedwhen vesicles form, break open, and leak a clear fluid. The lesionsusually scab over after a few days and heal themselves. While theselesions usually heal themselves in 5 to 14 days, they are unsightly andmay be very painful to those experiencing them. Herpes Simplex Viruslesions, other than cold sores, are similar in appearance and duration.

Most over-the-counter topical treatments for cold sores are topicalanesthetics to decrease pain, skin protectants (petroleum or zincoxide), antiseptics, or herbal remedies. Most of these topicaltreatments attempt to reduce the pain, discomfort and appearance of thecold sore but usually have little effect on the duration of the lesion,in addition, antiviral medications have been developed in an attempt toreduce the occurrence of lesion outbreaks and attempt to subvert theviral activity in the body. Many of these antiviral medications areadministered orally. Antiviral medications have also been developed astopical treatments in an attempt to slow down the activity of the viruswithin the lesion and are usually most effective if administered priorto the formation of the vesicles. Two well known and commerciallyavailable antiviral compounds are Penciclovir and Acyclovir.

Penciclovir is generally poorly adsorbed orally; therefore, it is oftenused more as a topical treatment. Penciclovir is often available byprescription in the pharmaceutical cream DENAVIR® which contains onepercent (1 %) Penciclovir. Use of 1% Penciclovir cream has been found toreduce the duration of a cold sore by an average of one-half day (anaverage of 4,5 days treated versus 5.0 days for untreated cold sores).Acyclovir is an antiviral that is administered through oral tablets,topical cream, intravenous injection and ophthalmic cream. A fivepercent (5%) Acyclovir topical cream is commercially available in thetopical medication ZORVIRAX™ cold sore cream. Similar to Penciclovir, 5%Acyclovir cream has also been clinically shown to reduce the duration ofa cold sore by an average of one-half day.

There have been other efforts made to improve the performance of thesedrugs when used to combat herpes viral infections. For example, U.S.Pat. No. 6,469,015 issued to Griffiths, et al., discloses the inclusionof solubilized Penciclovir in a topical formulation comprising propyleneglycol. This formulation was developed to increase the absorbance of thedrug at the skin and thereby provide and increased effective dosage tothe lesion area.

Synergistic combinations of antivirals with other compounds have beenreported. For example, U.S. Pat. No. 5,552,384 issued to Deziel, et al.,discloses the use of an antiviral nucleoside analog with aribonucleotide reductase inhibiting peptide derivative. Such acombination was reported to have increased antiviral activity withoutincreased toxicity.

The synergistic effects of combinations of multiple antivirals have alsobeen reported, but without suggesting the compounds disclosed herein.For example, Sutton, et al., “Activity of Penciclovir in Combinationwith Azido-Thymidine, Ganciclovir, Acyclovir, Foscarnet and HumanInterferons against Herpes-Simplex Virus-Replication in Cell-Culture,”Antiviral Chemistry and Chemotherapy, vol. 4, no. 2 pg, 85-94 (1992),discloses the use of Penciclovir with other antivirals includingacyclovir. However, the in-vitro studies conducted showed that thecombinations of antivirals had affects that were, “purely additive.”

Considering cold sores usually have a duration of 5-14 days, a one-halfday reduction in the duration of a cold sore resulting from treatmentwith antiviral compounds known in the prior art provides littleimprovement over not implementing any treatment at all. As such, thereIs a long-felt need in the art to provide a therapeutic compound toreduce the duration and scope of lesions resulting from the HerpesSimplex Virus, One embodiment being, a treatment that will drasticallyreduce the duration of a cold sore when vesicles have already appearedand a treatment that will prevent the formation of vesicles and a lesionwhen applied in the prodromal stage.

SUMMARY OF THE INVENTION

The present invention is generally directed toward therapeuticcompositions for treating lesions caused by Herpes Simplex Virus(“HSV”). The composition of the present invention meets a long felt needin the art of providing a treatment for lesions that result from HSVthat drastically reduces the duration of a cold sore when vesicles havealready appeared and a treatment that will prevent the formation ofvesicles and a lesion when applied in the prodromal stage. The presentinvention is a mixture of at least two active ingredients that result inprevention of the appearance of a cold sore when applied in theprodromal stage and also drastically reduces the duration of a lesionresulting from HSV-1 or HSV-2 after the vesicles or a lesion hasappeared. The therapeutic composition of the present invention comprisesa mixture of Acyclovir (“ACV”), Penciclovir (“PCV”), and dimethylsulfoxide (“DMSO”). The therapeutic compositions of the presentinvention include various concentrations of the at least threeingredients. Further, the composition of the present invention mayinclude inactive ingredients.

One non-limiting embodiment of the present invention is a compositionincluding about 3.75% of ACV, about 0.75% PC Y. and about 10% DMSO byweight. Other and further embodiments and objects of the invention,together with the features of novelty appurtenant thereto, will appearin the course of the following description.

DETAILED DESCRIPTION OF THE INVENTION

There is provided herein a therapeutic composition that prevents theformation of a lesion resulting from Herpes Simplex Virus (“HSV”) whenadministered in the prodromal stage and greatly reduces the duration ofa lesion resulting from infection with HSV when administered after thelesion has appeared. The therapeutic composition of the presentinvention generally includes a mixture of three antiviral compoundsblown in the art to topically treat lesions caused by HSV, Further, thepresent invention may contain inactive ingredients that facilitate theadministration of the composition of the present invention or make thecomposition of the present invention more commercially desirable,

The present invention includes a mixture of various concentrations ofthe following compounds: Acyclovir (“ACV”), Penciclovir (“PCV”), anddimethyl sulfoxide (“DMSO”). ACV and PCV are known antiviral compoundsin the that may be beneficial in treating lesions caused by HSV. BothPCV and ACV are commercially available for the treatment of HSV-1 andHSV-2 infections and can be administered through a variety of knownmethods which may include, but are not limited to oral tablets, topicalcream, intravenous injection and ophthalmic cream. DMSO is a membranepenetrant that may be particularly beneficial when used in conjunctionwith ACV and PCV. The composition of the present invention may alsocontain inactive ingredients to facilitate administration or make thecomposition more commercially desirable,

Acyclovir (“ACV”) is also known by its official IUPAC name,2-amino-9-((2-hydroxethoxy)methyl)-1H-purin-6(9H)-one. ACV has amolecular formula of C₈H₁₁N₅O₃ and the following molecular diagram:

ACV is a synthetic purine nucleoside analogue that has shown both invitro and in vivo effectiveness in inhibiting the replication of bothHSV-1 and HSV-2. ACV is called a prodrug because it is administered inan inactive or less active form and then metabolized into its activespecies after administration. While no mechanism of action is meant tobe limiting, it is believed that the viral enzyme thymidine kinaseencoded by HSV converts ACV into acyclovir monophosphate. Themonophosphate is subsequently converted into diphosphate by cellularguanylate kinase and further into triphosphate by a number of cellularenzymes. Because ACV is phosphorylated into its active form only by theviral specific thymidine kinase, the active triphosphate state isconfined to only the virus infected cells. Acyclovir triphosphate hasbeen shown to stop the replication of herpes viral DNA in vitro. As aresult, HSV DNA replication is stopped by the ACV derivative in threeways: (1) competitive inhibition of viral DNA polymerase, (2) the DNAchain incorporates the acyclovir triphosphate which terminates the DNAchain, and (3) the viral DNA polymerase is inactivated,

Known ACV administration methods include: oral (in tablets), topicalintravenous, and ophthalmic. ACV is thought to have poor oralbioavailability and therefore, topical or intravenous administration maybe Implemented to have the greatest dosage efficiency. Commonly, ACV iscommercially available in 200 mg, 400 mg, 800 mg, and 1 gram tablets aswell as a 5% topical cream. A five percent (5%) Acyclovir topical creamis commercially available in the topical medication ZORVIRAX™ and isused primarily for labial herpes simplex (cold sores). In thiscommercially available product, 5% ACV by itself has been clinicallyfound to reduce the duration of a lesion by only 0.5 days on average.

In one embodiment of the composition of the present invention, theamount of ACV in the mixture will range from about 0.1% to 40% by weightof the total mixture. In one embodiment of the composition of thepresent invention, the amount of ACV in the mixture will range fromabout 1% to 10% by weight of the total mixture. In another embodiment ofthe composition of the present invention, the amount of ACV in themixture will range from about 2% to 5% by weight of the total mixture.Further, an embodiment of the composition of the present invention willcontain about 3.75% ACV by weight of the total mixture.

Penciclovir (“PCV”) is also known by the official IUPAC name as2-amino-9-[4-hydroxy-3-(hydroxymethyl) butyl]-6,9-dihydro-3H-purin-6-one. PCV has a molecular formula of C₁₀H₁₅N₅O₃, and is asynthetic acyclic guanine derivative with a structure as follows:

Similar to ACV, PCV is believed to be phosphorylated by thymidine kinaseto a monophosphate form, which in turn is then converted to an activestate, penciclovir triphosphate, by cellular kinases. In vitro, HSV DNAsynthesis and replication are inhibited by Penciclovir triphosphatesinhibiting HSV polymerase competitively with deoxyguanosinetriphosphate. Because PCV is phosphorylated into its active form only bythe viral specific thymidine kinase, the active triphosphate state isconfined to only the virus infected cells.

PCV administration may include oral (in tablets), topical, intravenous,and ophthalmic. Commonly, PCV is most widely commercially available in a1% topical cream under the name DENAVIR®. The topical cream is availablecommercially by prescription and is used topically primarily for labialherpes simplex (cold sores). In this commercial embodiment, PCV byitself has been clinically found to reduce the duration of a lesion byonly 0.5 days on average.

PCV and ACV are similar compounds and inhibit HSV DNA replication inmuch the same way. The difference between the two; however, is that thetriphosphate of PCV has a very long intracellular half-life whencompared to ACV's triphosphate. Therefore, it takes a lowerconcentration of PCV per dose than ACV to achieve the same results. Thisdifference explains the commercial topical compounds containing 5% ACVin ZORVIRAX™ versus 1% PCV in DENAVIR®.

In one embodiment of the composition of the present invention, theamount of PCV in the mixture will range from about 0.1 % to 40% byweight of the total mixture. In one embodiment of the composition of thepresent invention, the amount of PCV hi the mixture will range fromabout 0.25% to 5% by weight of the total mixture. In another embodimentof the composition of the present invention, the amount of PCV in themixture will range from about 0.5% to 1.5% by weight of the totalmixture. Further, an embodiment of the composition of the presentinvention will contain about 0.75% PCV by weight of the total mixture.

DMSO is an aprotic polar solvent. DMSO penetrates skin and is misciblein a variety of organic solvents and water. While it is not clear, DMSOmay aid in the permeation of ACV and/or PCV through the skin in an areaproximate to an HSV lesion. Applicants have anecdotally observed anunexpectedly significant clinical improvement in patients with HSVlesions treated with a formulation of ACV, PCV, and DMSO.

In one embodiment of the composition of the present invention, theamount of DMSO in the mixture will range from about 1% to 40% by weightof the total mixture. In one embodiment of the composition of thepresent invention, the amount of DMSO in the mixture will range fromabout 2% to 20% by weight of the total mixture. In another embodiment ofthe composition of the present invention, the amount of DMSO in themixture will range from about 5% to 15% by weight of the total mixture.Further, an embodiment of the composition of the present invention willcontain about 10% DMSO by weight of the total mixture.

The composition of the present invention may also include inactiveingredients that facilitate administration of the composition of thepresent invention or make the present invention more commerciallydesirable. Such inactive Ingredients may include but are not limited to:purified water, mineral oil, propylene glycol, white petrolatum, aloe,cetyl alcohol, colloidal silicon dioxide, carnauba wax, ethylhexylpalmitate, isopropyl lanolate, isopropyl myristate, medium chaintriglycerides, methylparaben, octyldodecanol, alcohol, paraffin, phenyltrimethicone, polyhydroxystearic acid, propylparaben, saccharin, silica,titanium dioxide, vitamin E acetate, white wax, bee's wax, camphor,menthol, lanolin, cocoa butter, botanical extracts, saline solution, ortopical anesthetics. Other ingredients may be included in increase theefficiency of topical delivery. Such ingredients may include membranepentrants such as dimethyl sulfoxide (DMSO). In some embodiments atherapeutic compound may also include ingredients having otherfunctionalities. For example, a variety of antiseptics may be used.While the synergistic combinations of compounds described herein areexemplary, other compounds having antiviral properties may be added. Forexample, lysine may be added to the composition and is known to havesome anti-HSV activity.

The composition of the present invention may be administered topically,intravenously, or orally; however, the present invention is not limitedto a particular method of administration. One embodiment includes atopical formulation of the composition of the present invention whereinabout 3.75% ACV, about 0.75% PCV, about 10% DMSO, and the remainingabout 85.5% comprising inactive ingredients of white petrolatem,propylene glycol, and mineral oil are mixed together such that theactive ingredients are evenly disbursed. At the first onset of symptomsof a lesion caused by HSV-1 or HSV-2 (a cold sore), the topicalformulation is applied to the infected, area every 2 hours while awake,

The composition of the present invention has a synergistic additiveeffect that constitutes results unexpected in the art. The threecompounds act synergistically to reduce the duration of the cold sore bya clinically significant amount of time. If the composition of thepresent invention is applied as directed, when the prodromal symptomsappear and before the vesicles of the lesions erupt, the result expectedis only slight redness and no eruption of the vesicles. Therefore, thecomposition of the present invention may prevent the outbreak fromcontinuing, or the viral cycle from, continuing at the point of contactfor immediate healing. The composition of the present invention has thepotential to completely prevent an outbreak of a cold sore caused byHSV-1 or HSV-2 and substantially reduce or eliminate associated pain.This result is unexpected in the art because all known treatments forcold sores resulting from HSV-1 or HSV-2 have no known curative effectsand only have been shown to slightly reduce the duration of and the paincaused by a lesion.

Even if the composition of the present invention would be applied aftervesicles have appeared and erupted, the composition of the presentinvention is expected to greatly reduce the healing time such that, inmost circumstances, the full blown cold sore would be reduced to onlyredness by the third day of application. When compared to the averageduration of a cold sore of 4.5 days of the known compounds in the priorart (only 0.5 days less that no treatment at all), the composition ofthe present invention's expected healing time is an unexpected result ofthe combination of ACV, PCV and DMSO, Treatment with the compound isexpected to significantly reduce the length of outbreaks.

In some embodiments, the mass ratio of ACV to PCV may in a range ofabout 1:1 to 10:1. In some exemplary embodiments, the mass ratio of ACVto PCV may be in a range of about 2:1 to 7:1. In yet other embodiments,the mass ratio of ACV to PCV may be about be 5:1. In some of thesevarious embodiments, the mass ratio of ACV to DMSO may be about 1:10 to1:2. In some embodiments, the mass ratio of ACV to DMSO may be about1:4.

In some embodiments, the composition may include ACV, PCV, and DMSO inthe absence of any other active ingredient.

EXAMPLES Example 1:

In a first example, a patient may present with a lesion in the vesiclestage before any treatment had been attempted. Treatment included fourapplications of a compound including 3.75% ACV, about 0.75% PCV, about10% DMSO may be administered over two days.

The patient of Example 1, based on the anecdotal observations to date,would be expected to report that the normal course of an outbreak,without treatment, would begin with a lesion in the vesicle stage andproceed to a lesion of such size that roughly half of the lip would becovered. The patient may also report significant pain associated withprevious outbreaks was avoided with the treatment,

In anecdotal testing, post-treatment outbreaks were not observed for theduration of the follow-up period (about one year). The lack of outbreaksover such a timeframe was unusual for this patient, and it does notappear that such effective viral repression has been achieved in thepast with a topical treatment.

While the examples included herein relate to the treatment of HSV-1related lesions around the mouth, the disclosed compounds may be usefulfor treating other HSV-1 and HSV-2 lesions regardless of the region ofthe body where they occur,

From the foregoing, it will be seen that this invention is one welladapted to attain all ends and objects hereinabove set forth togetherwith the other advantages which are obvious and which are inherent tothe structure. It will be understood that certain features andsubcombinations are of utility and may be employed without reference toother features and subcombinations. This is contemplated by and iswithin the scope of the claims.

Since many possible embodiments may be made of the invention withoutdeparting from the scope thereof, it is to be understood that ail matterherein set forth or shown in the accompanying drawings is to beinterpreted as illustrative, and not in a limiting sense.

What is claim is:
 1. A therapeutic composition to treat infectionscaused by the Herpes Simples Virus comprising: Acyclovir, Penciclovir;and dimethyl sulfoxide,
 2. The therapeutic composition of claim 1,wherein said mixture contains about 0.1 to 40% Acyclovir.
 3. Thetherapeutic composition of claim 1, wherein said mixture contains about0.1 to 40% Penciclovir.
 4. The therapeutic composition of claim I,wherein said mixture contains about 5 to 20% dimethyl sulfoxide.
 5. Thetherapeutic composition of claim 1, wherein a mass ratio of Acyclovir toPenciclovir is in a range of about 1:1 to 10:1.
 6. The therapeuticcomposition of claim 1, wherein a mass ratio of Acyclovir to Pencicloviris in a range of about 2:1 to 7:1.
 7. The therapeutic composition ofclaim 1, wherein a mass ratio of Acyclovir to Penciclovir is about 5:1.8. The therapeutic composition of claim 1, wherein a mass ratio ofAcyclovir to dimethyl sulfoxide is in a range of about 1:10 to 1:2. 9.The therapeutic composition of claim 1, wherein a mass ratio ofAcyclovir to dimethyl sulfoxide is about 1:4.
 10. The therapeutic composition of claim 1, further comprising at least one additionalantiviral ingredient.
 11. The therapeutic composition of claim 1,further comprising an ingredient selected from a group consisting ofmineral oil, propylene glycol, and white petrolatem.
 12. The therapeuticcomposition of claim 1, further comprising an additional antiviralIngredient.
 13. A therapeutic composition to treat infections caused bythe Herpes Simples Virus comprising: up to about 3.75% Acyclovir; up toabout 2% Penciclovir; up to about 20% dimethyl sulfoxide; and at leastone inactive ingredient wherein the inactive Ingredient is selected froma group consisting of mineral oil, propylene glycol, and whitepetrolatem.
 14. The therapeutic composition of claim 13, comprising upto about 2.5 % Acyclovir.
 15. The therapeutic composition of claim 13,comprising up to about 1% Pencyclovir.
 16. The therapeutic compositionof claim 13, comprising up to about 10% dimethyl sulfoxide.
 17. Atherapeutic composition to treat infections caused by the Herpes SimplesVirus consisting essentially of: a pharmaceutically acceptable carrier;Acyclovir; Penciclovir; and dimethyl sulfoxide;
 18. A method of treatinglesions related to HSV infection in an animal or human comprisingapplying the therapeutic composition of claim 1, to said lesions.
 19. Amethod of preventing the eruption of lesions related to HSV infection inan animal or human comprising applying the therapeutic composition ofclaim 1 to the animal or human.